The field of the invention relates to electroactive pores, e.g., for use in the delivery of therapeutic agents.
Certain conditions, such as hypertension, diabetes, hemophilia and other chronic conditions, can be especially taxing because they require ongoing therapeutic intervention. In many instances, patients can suffer not only the inconvenience caused by exceedingly frequent drug administration, but can also risk regular exposure to both toxic and ineffective plasma levels of drugs; toxic levels occurring soon after the drug is administered and ineffective levels occurring prior to the next scheduled administration.
Efforts have been directed toward development of controlled-release preparations such as matrixes, coated granules, or microcapsules. In addition, systems for delivery of a certain amount of drug per unit time have been developed. Systems that release drugs at a constant rate (zero-order drug delivery) are known.
One type of delivery system uses on an infusion pump for drug delivery.
In general, one aspect of the invention features a device including a member, an electroactive polymer and a biologically active transfer agent (BETA) associated with the electroactive polymer. The member has a pore passing therethrough, and the electroactive polymer is disposed so that when the electroactive polymer has a first state of charge a therapeutic agent has a first ability to pass through the pore, and when the electroactive polymer has a second state of charge different from the first state of charge the therapeutic agent has a second ability to pass through the pore different than the first ability to pass through the pore.
As used herein, the term xe2x80x9celectroactive polymerxe2x80x9d refers to an electrically conductive polymer. In some embodiments, an electroactive polymer is a polymer whose conductivity has been modified with one or more electron acceptor and/or electron donor dopants so that the electrical conductivity of the polymer is greater than that of the undoped polymer. In certain embodiments, an electroactive polymer is preferably substantially linear, e.g., contains few, if any, branch points or cross-links. Examples of electroactive polymers are disclosed in, for example, U.S. Pat. No. 4,519,938, which is hereby incorporated by reference.
In another aspect, the invention generally features a method of administering a therapeutic agent. The method includes passing the therapeutic agent through a device. The device includes a member, an electroactive polymer and a biologically active transfer agent (BETA) associated with the electroactive polymer. The member has a pore passing therethrough, and the electroactive polymer is disposed so that when the electroactive polymer has a first state of charge a therapeutic agent has a first ability to pass through the pore, and when the electroactive polymer has a second state of charge different from the first state of charge the therapeutic agent has a second ability to pass through the pore different than the first ability to pass through the pore. The method optionally includes charging the electroactive pore.
In a further aspect, the invention generally features a method of administering a therapeutic agent. The method includes charging an electroactive polymer. The electroactive pore is disposed relative to a pore so that when the electroactive polymer has a first state of charge the therapeutic agent has a first ability to pass through the pore, and when the electroactive pore has a second state of charge different from the first state of charge the therapeutic agent has a second ability to pass through the pore different than the first ability to pass through the pore. The method also includes passing the therapeutic agent through the pore.
In certain embodiments, the electroactive polymer is at least partially disposed within the pore, e.g, entirely disposed within the pore. In some embodiments, the electroactive polymer is at least partially disposed outside the pore, e.g., entirely disposed outside the pore.
The BETA can be associated with the electroactive pore so that electronic charge can be transferred between the BETA and the electroactive pore. The BETA can be associated with the electroactive polymer by, e.g., crosslinking, ionic bonding, covalent bonding and combinations thereof.
In general, the BETA can be an enzyme or a functional derivative of an enzyme, e.g., glucose oxidase or a functional derivative thereof.
The device can further include one or more mediators to assist in transferring electric charge, e.g., one or more mediators to assist in transferring electric charge between the member and the electroactive pore and/or one or more mediators to assist in transferring electric charge between the electroactive pore and an analyte, e.g., glucose.
The device can further include a reservoir in fluid communication with the pore. The reservoir can contain a therapeutic agent. The reservoir can be constructed from essentially any material(s) that can be molded to form a cavity. The material(s) can be flexible or inflexible.
In some embodiments, the first state of charge has a lower absolute value than the second state of charge, and the first ability of the analyte to pass through the pore is greater than the second ability of the analyte to pass through the pore.
The electroactive polymer can include aromatic molecules. The electroactive polymer can include a series of alternating single and double bonds, e.g. thiophen, phenylene diamine, pyrrole, aniline, or substituted derivatives thereof. In some embodiments, the electroactive polymer is polyaniline.
In certain embodiments, the electroactive polymer is polyaniline, and the BETA is glucose oxidase.
The membrane can be a layer of a material.
The device can further include an attachment member, e.g., an adhesive pad, a belt and/or a strap, to attach the device to a patient.
The device can also include a relatively positive element, e.g., an electrode, and a relatively negative element, e.g., an electrode, that together form a bias current within the device.
In certain embodiments, e.g., when the device is used in vivo, the device can further include a microporous needle that can extend from the surface of the skin to the interstitial fluid or to the capillary bed. Similarly, the device can include a cathether that can extend from the surface of the skin to the interstitial fluid or to the capillary bed.
The member can be electrically conductive, e.g., contain an electrically conductive material, including metals or alloys, such as gold, platinum, palladium, iridium, or combinations thereof. The member can be formed predominantly of electrically conductive material, and/or the member can be formed of an electrically non-conductive (or relatively poorly conductive) material coated with a metal or alloy, e.g., gold, platinum, palladium, or iridium, or a combination thereof.
The manner in which the electroactive polymer is charged can be varied. For example, the charge on the electroactive pore can be fixed, variable or cyclical.
Therapeutic agents that can be used in the devices and methods of the invention include, for example, vaccines, chemotherapy agents, pain relief agents, dialysis-related agents, blood thinning agents, and compounds (e.g., monoclonal compounds) that can be targeted to carry compounds that can kill cancer cells. Examples of such agents include, insulin, heparin, morphine, interferon, EPO, vaccines towards tumors, and vaccines towards infectious diseases.
The device can be used to deliver a therapeutic agent to any primate, including human and non-human primates. The device can be used to deliver an agent, e.g., a therapeutic agent to an animal, e.g., a farm animal (such as a horse, cow, sheep, goat, or pig), to a laboratory animal (such as a mouse, rat, guinea pig or other rodent), or to a domesticated animal (such as a dog or cat). The animal to which the therapeutic agent is being delivered can have any ailment (e.g., cancer or diabetes). It is expected that the device may be most useful in treating chronic conditions. However, the device can also be used to deliver a therapeutic agent (such as a vaccine) to an animal that is not suffering from an ailment (or that is suffering from an ailment unrelated to that associated with the therapeutic agent). That is, the device can be used to deliver therapeutic agents prophylactically.
The devices and methods of the invention can be used to individually tailor the dosage of a therapeutic agent to a patient.
The devices and methods of the invention can allow for outpatient treatment with increased convenience, such as, for example, without the use of an I.V.
Devices described herein can be advantageous because they can be used to promote maintenance of the concentration of a therapeutic agent in a patient""s plasma within a safe and effective range. Moreover, the device can release therapeutic agents in response to the concentration of an analyte in the patient""s system. Thus, the rate of drug delivery can be appropriate for the patient""s physiological state as it changes, e.g., from moment to moment.
Additional advantages are provided by the design and use of the devices of the invention. For example, where a BETA are positioned within or adjacent one or more pores of a member, the BETA can be protected from external influences, such as those arising when the device is handled and used. This protection can be particularly advantageous, e.g., when the BETA is a protein, such as glucose oxidase. In such an event, it can be desirable to maintain the protein""s tertiary structure in order to retain maximal biological activity. In addition, because the device can be easily replaced (e.g., a patient can apply a device to the skin every day, or every other day) the amount of a therapeutic agent (e.g. insulin) within the device can be limited. Thus, in the unlikely event the device should malfunction, the risk of serious overdose can be limited. The patient could receive, e.g., at most, only as much of the therapeutic agent as would be delivered over one or two days of administration. In the event insulin is being delivered, in some embodiments the overdose could be limited to as little as about 25 units of insulin.